The present invention generally relates to novel compositions, methods, devices and kits for the prevention and/or treatment of prostate disorders in mammals. The present invention also generally relates to devices for the administration of therapeutic compounds to mucosal membranes in the lower urinary tract of mammals.
Diseases of the prostate are common maladies of male mammals, especially men. They include benign prostatic hypertrophy (BPH), carcinoma of the prostate (CaP), prostadynia, prostatitis, and chronic prostatitis.
The steadily increasing age of the world""s population is a testament to the success of modem medicine and preventive care. However, this success has brought with it the problem of a greater number of men suffering from BPH, CaP and other prostate disorders.
The incidence of BPH increases steadily with age and is a nearly universal autopsy diagnosis of men in the 8th and 9th decades of their life (HA Guess, xe2x80x9cEpidemiology and natural history of benign prostatic hyperplasia,xe2x80x9d Urol Clin North Am. 1995; 22:247-261). At least 75% of men over the age of 70 have symptoms consistent with BPH and about 30% of men may have surgery to treat BPH during their lifetime. The Baltimore Longitudinal Study of Aging found that almost 60% of men aged 60 years or older were given a clinical diagnosis of BPH (HM Arrighi et al, xe2x80x9cNatural history of benign prostatic hyperplasia and risk of prostatectomy. The Baltimore Longitudinal Study of Aging,xe2x80x9d Urology 1991; 38 Suppl. 1:4-8). Other mammals that are known to exhibit a high incidence of BPH include dogs and Syrian Hamsters.
Carcinoma of the prostate is now the most common malignancy of men and shows the same pattern of increasing incidence with age as does BPH (SL Parker et al, xe2x80x9cCancer statistics,xe2x80x9d CA Cancer J Clin 1997; 45:5-27). Indeed, it has been said that every man would develop carcinoma of the prostate (CaP) if he lived long enough.
The bladder serves as a storage vessel for urine produced by the kidneys until the mammal desires to eliminate the urine by voiding. The urethra is a tube or conduit through which urine flows from the bladder to the exterior of the mammal. In man, the urethra is composed of three main divisionsxe2x80x94the prostatic, the membranous and the penile segments (FIG. 1).
The prostate gland encases the urethra as it exits the bladder. This anatomical arrangement in which the urethra is completely surrounded by the prostate makes it susceptible to compression by the prostate. Any encroachment upon the lumen of the prostatic urethra will result in obstruction to the flow of urine.
BPH causes obstruction to the flow of urine by two major mechanisms that are distinct componentsxe2x80x94a static (fixed) component due to the hypertrophied prostate tissue and a dynamic component due to excessive tone in the smooth muscle tissues of the prostate. Both of these mechanisms cause compression and obstruction of the urinary outflow tract. The pathophysiology of BPH involves hypertrophy of the glandular and stromal tissue of the peripheral zone of the prostate and the periurethral area that surrounds the urethra (see FIG. 2) leading to narrowing of the lumen and mechanical obstruction of the urinary outflow tract. Pathology findings on prostate tissue from patients with BPH include fibrosis and hyperplasia of the musculature and gland structure of the prostate.
Patients with BPH commonly complain of symptoms that include difficulty initiating urination (hesitancy), difficulty terminating urination (dribbling), frequent urination secondary to an inability to completely empty the bladder of urine (frequency) and having to awaken in the night to empty the bladder (nocturia). Since no methods are known to prevent or cure BPH, the primary focus of treating BPH is to alleviate these complaints and thereby improve the patient""s quality of life.
Two measures of the degree of outflow tract obstruction that are commonly followed in studies of patients with BPH are the subjective complaints of BPH symptoms and measures of the ability to empty the bladder of urine (urodynamics). Urodynamics studies consist of measuring the rate of urine flow and the quantity of urine produced as the patient urinates into a container placed on an electronic scale. A graph of urine flow versus time is produced and the patient""s urine flow measurements may then be compared to population derived average urine flow measurements. More complex urodynamics studies measure pressures produced by contraction of the bladder muscles during urination. One measure of the degree of urinary tract obstruction is the maximum or peak urinary flow rate as measured by urodynamics studies. FIG. 3 shows typical urodynamics studies. Peak urinary flow rates of less than 15 milliliters (mls) per second indicate significant urinary obstruction and flow rates of less than 5 mls/second are felt to be an indication for prompt surgical relief of the obstruction.
Prostate specific antigen (PSA) is a serum protease that is widely used as an indicator of disease severity in both BPH and CaP. Not only are prostatic tissues the only source of PSA but serum PSA levels closely correlate with the total amount of prostate tissue present in the body at any given time. Treatments that reduce the tumor mass in CaP or that induce regression of BPH will demonstrate a reduction in serum levels of PSA.
Current medical treatments of BPH include surgery; systemic therapy with alpha-adrenergic blocking agents such as doxazosin, terazosin, prazosin, alfuzosin, R(+)-terazosin, bunazosin, indoramin and tamulosin; alteration of testosterone metabolism; and therapy with an oral herbal medicine extracted from the saw palmetto (Serenoa repens). Huff (U.S. Pat. No. 5,760,054) discloses a number of more specific alpha 1C adrenergic receptor antagonists that may be utilized in the treatment of BPH.
Treatment of BPH with alpha-adrenergic blocking agents is believed to exert beneficial effects by reducing the adrenergic tone of the smooth muscle cells in the prostate via the alpha-1 receptors. Excessive alpha adrenergic tone in the prostatic smooth muscle cells results in a reversible narrowing of the diameter of the urinary outflow tract as it courses through the prostate. This dynamic component of BPH is believed to be the pathophysiology of BPH in men with small prostates. Oral administration of alpha blockers leading to decreased alpha-1 adrenergic tone is felt to result in relaxation of prostatic smooth muscle with a resultant functional improvement in obstructive urinary tract symptoms such as hesitation, dribbling and nocturia. Alpha-adrenergic blocking agents are therefore best used in men with small prostates where smooth muscle contraction is likely to be the primary contributor to the obstructive symptoms. A meta-analysis of placebo-controlled studies of alpha blockers shows improvement in the peak urinary flow rates by 1.5 ml/sec (LM Eri et al, xe2x80x9cAlpha-blockade in the treatment of symptomatic benign prostatic hypertrophy,xe2x80x9d J Urol 1995; 154:923-934).
Another approach taken in the medical treatment of BPH involves altering the metabolism of testosterone. Testosterone is converted by 5alpha-reductase into dihydrotestosterone, a compound that stimulates tissue growth in the prostate. This enzyme exists in at least two isoenzyme forms, Type I and Type II. For reasons that are not known, the ratio of dihydrotestosterone to testosterone present in the blood increases with age. The conversion to dihydrotestosterone greatly increases the potency of testosterone in many tissues including the prostate. The growth of the prostate tissue in BPH is exacerbated by the increased ratio of dihydrotestosterone to testosterone that accompanies aging. Finasteride is a drug specifically developed to block the reduction of testosterone to dihydrotestosterone by 5alpha-reductase. Oral administration of finasteride is approved by the FDA as a treatment for the symptoms of BPH. Finasteride has a gradual onset of action resulting in a 70% reduction in serum dihydrotestosterone levels after daily dosing with 5 milligrams. Administration of finasteride for a period of 6-12 months is generally necessary to determine whether a patient with BPH will improve. Unfortunately, a minority of all patients with BPH improve on oral finasteride and the degree of improvement is relatively small. For example, two large clinical studies demonstrated an increase of only xcx9c1.6 mls/second in peak urinary flow rates with finasteride treatment. Meta-analysis of studies with finasteride demonstrate a 0.5 to 0.8 ml/sec average improvement in peak urinary flow rates compared to placebo (L M Eri et al, xe2x80x9cTreatment of benign prostatic hyperplasia. A pharmacoeconomic perspective,xe2x80x9d Drugs Aging 1997 Febuary; 10(2):107-18).
Another option that may be suggested for men with BPH is an oral herbal medicine preparation extracted from the saw palmetto (Serenoa repens). This preparation contains a variety of compounds that bind androgen receptors and demonstrate 5alpha-reductase inhibition in vitro. The mechanism of action is complex and may involve other pharmacologic activities. Several clinical studies indicate that extracts of Serenoa repens exhibit roughly the same amount of clinical symptom improvement and improvement in peak urinary flow as does finasteride (GS Gerber, xe2x80x9cSaw Palmetto in men with lower urinary tract symptoms:effects on urodynamic parameters and voiding symptoms,xe2x80x9d Urology 1998 June; 51(6):1003-7).
Each of these treatments has limitations and drawbacks. Most of the side effects of medical treatments stem from the systemic (oral) administration of a therapeutic agent to treat a very localized problem in the prostate. The alpha-adrenergic receptor antagonists may cause a significant decrease in the systolic blood pressure, syncope, orthostatic hypotension, asthenia, dizziness, headache, sleepiness, fatigue and impotence. A recent myocardial infarction, transient ischemic attack or cerebrovascular accident constitute relative contraindications to the use of alpha-blockers. The effect of alpha-blockers is usually apparent in the first two weeks of treatment and maximum clinical effects are seen in one or two months (L M Eri et al, Drugs Aging, op cit). Side effects of finasteride administration in men are primarily sexualxe2x80x94erectile dysfunction, decreased volume of ejaculate and loss of libido. Severe teratogenic effects on the fetus preclude the use of finasteride by men whose partner may conceive. Side effects of Serenoa repens therapy are generally the same as with finasteride.
The use of oral therapeutic compounds leads to exposure of all the tissues of the body in an attempt to reach the prostate gland. Local administration of a drug directly to the prostate is hampered by the fact that the prostate gland is an internal organ. The applicant believes that local therapy of the prostate has been achieved to date only by injection of drugs via a hypodermic needle directly into the prostate (A Morales, xe2x80x9cIntralesional administration of biological response modifiers in the treatment of localized cancer of the prostate: a feasibility study,xe2x80x9d Urology 1997 ; 50(4): 495-502). This method of administration is difficult, painful and potentially dangerous.
Administration of therapeutic compounds systemically also has severe drawbacks. Doses in systemic administration are much greater than one might otherwise need if a more direct route of administering drugs were possible. For example, a 40 gram prostate gland in an 82 kilogram (180.4 pounds) man constitutes only 0.05% of the total body mass. Thus, systemic therapy must expose 99.95% of the body to a pharmacologically active drug in order to reach therapeutic levels in the 0.05% of the targeted prostate tissue. Alpha receptors are present diffusely throughout the vascular system and in other organs of mammals. Thus, drugs given to block alpha receptors in the prostate will certainly result in inhibiting normal alpha receptor mediated physiologic functions throughout a mammal. Dihydrotestosterone exerts effects upon most tissues and organs in a male mammal. Thus, reductions in 5alpha-reductase activity systemically must result in other than the desired effects upon the growth of prostatic tissue. Administration of systemic therapy in order to treat the prostate is roughly analogous to painting a house in order to paint the window frame or to spraying a city with pesticides in order to eliminate insects in the city gardens.
Surgical treatment of BPH is the most common surgery of men in the developed countries of the world. In 1989, 400,000 men in the US underwent surgery of the prostate at a cost of greater than $3 billion (M A Kortt et al xe2x80x9cThe economics of benign prostatic hyperplasia treatment: a literature review,xe2x80x9d Clinical Therapeutics 1996; 18(6):1227-1241). The most common prostate surgery involves trans-urethral resection of the prostate (TURP), which is accomplished by resecting the prostatic tissues surrounding the urethra that cause obstruction through a large bore urinary catheter. One prospective randomized study of TURP demonstrated an increase in peak urinary flow of 7.0 ml/sec after surgery (R S Cowles et al xe2x80x9cA prospective randomized comparison of TURP to visual laser ablation of the prostate for the treatment of benign prostatic hypertrophy,xe2x80x9d Urology 1995 August; 46(2):155-600). A second multicenter study demonstrated an increase of 11.35 ml/sec (130%) in peak urinary flow rates following TURP. TURP gives a 4-8 times greater increase in peak urinary flow rates than does treatment with alpha blockers and a 9-22 times greater increase in peak urinary flow rate when compared to finasteride. This surgical procedure carries the usual attendant health risks of a major operation in addition to the complications of urinary incontinence and impotence. Approximately 15% of patients undergoing TURP are estimated to have serious complications and about 5% require a repeat operation after two years. (L M Eri et al, Drugs Aging, op cit). These limitations have spurred the development of a number of other approaches to remove the obstructing tissues with fewer complications such as microwave ablation, cryotherapeutic ablation and laser ablation of the prostate (see M Barba et al, xe2x80x9cNew technologies in transurethral resection of the prostate,xe2x80x9d Curr Opin Urol 2000 January; 10(1):9-14; A Koritt op cit and U.S. Pat. No. 6,102,929 as examples). Each new procedure has its individual complications and none has supplanted TURP. The applicant is unaware of any method presently available of treating BPH that can replace surgical removal of the excess prostatic tissue much less prevent the nearly universal development of BPH in aging men.
Thus, there is a pressing need for new and improved methods, compositions and devices to prevent and treat prostate disorders in mammals. Compositions and methods of treatment that exhibit more rapid onset of action, more potent effects on peak urinary flow rates, less systemic side effects, without deleterious effects upon sexual function or urinary continence are needed. Since aging is also associated with increasing incidences of heart attack and strokes, methods of treating BPH that do not exacerbate cardiovascular or cerebrovascular disease are particularly needed. There is also a need for routes of administration for drugs that minimize systemic exposure. There remains a need for compositions and kits useful for preventing and treating prostate disorders in mammals.
It is one object of the present invention to provide compositions for preventing and/or treating prostate disorders in mammals.
It is another object of the present invention to provide methods for preventing and/or treating prostate disorders in mammals.
It is another object of the present invention to provide devices to deliver therapeutic compounds to the mucosal membranes of the lower urinary tract.
It is another object of the present invention to provide kits for preventing and/or treating prostate disorders in mammals.
These objects have been obtained by the inventor""s discovery that administering certain therapeutic compounds to mucosal membranes of the lower urinary tract of a mammal is effective in preventing and/or treating prostate disorders.
The present invention has demonstrated a method of treating BPH with efficacy within one hour of treatment, a surprisingly rapid response compared to weeks or months needed to demonstrate efficacy with present therapies. Further, one treatment has normalized urinary flow in some patients given this therapy. In several cases, the present invention has given improvement in urinary flow rates that exceed reports of improvement with surgery. This invention involves minimal intervention when compared to present therapies and offers hope for the prevention and/or treatment of prostate disorders.
Additional aspects, features, embodiments and advantages of the present invention will be set forth, in part, in the description that follows, or may be learned from practicing or using the present invention. The objects and advantages may be realized and attained by means of the features and combinations particularly pointed out throughout this description and the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not to be viewed as being restrictive of the invention as claimed.